Cardiovascular diseases (CVD) are the major causes of morbidity and mortality in the US and their risks are determined by non-modifiable (i.e., genetic) and modifiable factors (i.e., plasma lipid levels). It is well established that low levels of high-density lipoprotein cholesterol (HDL-C) are associated with increased CVD risk. A key determinant of HDL metabolism is hepatic lipase (HL), an enzyme that catalyses the hydrolysis of triglycerides and phospholipids in lipoproteins. Within the hepatic lipase (LIPC) gene at position -514 exists a common C/T polymorphism. The -514TT genotype is associated with an approximate 40% decrease in HL activity and increased HDL-C levels. However, this effect is variable among populations, suggesting gene- environment interactions. One of this grant's earlier key findings is that the -514 polymorphism shows a statistically significant interaction between HDL-C levels and dietary fat intake in Whites. Moreover, we replicated the findings in an Asian population. What remains to be demonstrated is whether these interactions occur when subjects modify their dietary fat intake and if so, what mechanisms are involved. Thus, the primary goal of this proposal is to use an interventional setting to thoroughly evaluate interactions between LIPC gene variants, changes in dietary fat intake and plasma lipid levels, inflammation markers and endothelial function. Moreover, we hypothesize that minorities, such as Hispanics, due to the enrichment of the -514 T allele (approximately 0.36) are more susceptible to the effects of these gene-diet interactions. Hence, we propose a randomized, cross over, two-phase diet intervention aimed at assessing the impact of consuming different levels of dietary fat (15% and 37%, respectively, 6 weeks each) on plasma HDL related measures in Caribbean Hispanic subjects (n=80;40 CC and 40 TT). Our main hypothesis is that CC subjects respond to increases in the % of energy consumed as fat with increases in HDL-C levels. Conversely, in TT subjects, such dietary change results in decreases in HDL-C levels and worsening of endothelial function. Therefore, T subjects will have an elevated CVD risk when consuming high fat diets. Moreover, given the high frequency of the T allele in Hispanics, this interaction could account for some of the increase in CVD risk seen after acculturation. This evidence-based knowledge will contribute to a rational approach toward more effective dietary recommendations aimed to decrease health disparities and to a better CVD prevention.